Resolution of racemic aryl-substituted aliphatic carboxylic acids has been described in the literature. Kaiser et al., J. Pharm. Sci., Vol. 65, No. 2, 269-273 (February 1976) formed the S(-)-.alpha.-methylbenzylamine salt of S(+)-ibuprofen, removed it from the reaction mixture by filtration, and recrystallized it from isopropanol and then from methanol. After acidifying the 3N aqueous sulfuric acid and extracting with ether, S(+)-ibuprofen was obtained, m.p. 50.14 52., [.alpha.].sub.D +57., with 95% optical purity as determined by GLC analysis. Cox et al., J. Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (March 1985), using the Kaiser et al. method, were able to obtain an S(+)-ibuprofen preparation which was 99% S isomer and 1% R isomer (w/w).
Other methods of separating the enantiomers of racemates can be effected by preparing a salt of the acid with an alkaloid or similar resolving agent such as cinchonidine, then separating the products by fractional crystallization from a solvent in which the salt of the dextrorotatory isomer is less soluble. The (+)-salt can then be acid cleaved to yield pure enantiomer. See, for example, U.S. Pat. No. 4,209,638 issued Jun. 24, 1980, and U.S. Pat. No. 3,637,767 issued Jan. 25, 1972, which relate to resolution of naproxen and related compounds.
U.S. Pat. No. 5,015,764 discloses and claims a process for increasing the amount of the desired enantiomer obtained from a racemic mixture of C.sub.1 to C.sub.6 linear or branched aliphatic carboxylic acid or ester thereof. The process comprises: (i) forming a mixture comprising the racemic mixture of the C.sub.1 to C.sub.6 linear or branched aliphatic carboxylic acid or ester thereof and an organic or inorganic solvent; (ii) treating said salt solution with a chiral organic nitrogenous base; (iii) precipitating from the reaction solution produced in the treatment of step (ii) a crystalline material that is comprised of greater than 50% of one diastereomeric salt; and (iv) separating said diastereomeric salt. The disclosure of this patent is incorporated herein by reference.
According to the process of the present invention, an improvement of the above process has been discovered. Reaction steps (i), (ii) and (iii) are carried out as disclosed. At this point in the reaction sequence, a two-phase mixture is produced that is essentially the solid diastereomeric salt and the remaining reaction liquid. The solid is dispersed in near emulsion form throughout the liquid. It is typically separated by filtration leaving the mother liquor filtrate and solid filtered residue. The residue requires numerous recrystallizations before a product of satisfactory purity is obtained. This process of successive crystallization significantly reduces the amount of final product recovery of satisfactory purity. The conventional separation processes are inconvenient and time consuming, disadvantageously producing multiple process streams and reducing yield of the product significantly.
It has now been discovered that an improved crystalline product can be obtained, at significantly higher yields, from the crystalline material of step iii) by adding to such crystalline material a solution of the same C.sub.1 to C.sub.6 linear or branched aliphatic carboxylic acid or ester thereof. It should be understood that the term "racemic mixture" as used throughout this specification is intended to include enantiomer mixtures of 1:1, S to R ratio, through to mixtures of 99% of one of said enantiomers (an enantiomerically enriched racemic mixture).
While not wishing to be bound by the following, it is known that the crystalline material precipitated from the treatment step ii) is a mixture of enantiomeric salts of the carboxylic acids (or esters thereof), the mixture being of greater than 50% concentration in one of the salts. The precipitated mixture has a high concentration of the less soluble enantiomer in the solvent used to form the salt solution of step i). The more soluble enantiomer remains in solution. As such, the slurry formed from step iii) is an equilibrium mixture of the enantiomeric salts. Addition of a solution of the racemic mixture of the aliphatic carboxylic acid upsets this equilibrium by first interacting with the more soluble diastereomeric salt causing the newly formed, less soluble enantiomer to precipitate. This interaction/precipitation continues until a new equilibrium is established. However, the end result is that the amount of less soluble enantiomer in the crystalline material is increased. As such, the process of the present invention is a purification or optical enrichment process with significantly higher recoveries in yield.
Preferably, under these reaction conditions, the solvent used for dissolving the racemic mixture of the aliphatic carboxylic acid or ester thereof is a C.sub.5 to C.sub.12 linear or branched hydrocarbon optionally substituted with one or more halo groups or it is an aromatic hydrocarbon optionally substituted with one or more C.sub.1 to C.sub.6 linear or branched alkyl, nitriles, amides, halo or hydroxyl group. Most preferably, the solvent is selected from the group consisting essentially of hexanes, heptanes, octane, benzene, toluene, xylenes, methanol, ethanol, propanols, butanols, pentanols, hexanols, linear or branched amides, diamides and substituted amides or mixtures thereof.
The C.sub.1 to C.sub.6 linear or branched aliphatic carboxylic acids and esters useful in the improved process of the present invention have the formula ##STR1## where R.sub.1 is hydrogen or C.sub.1 to C.sub.6 linear or branched alkyl or substituted linear or branched alkyl; R.sub.2, R.sub.3 and R.sub.4 are independently the same or different and are hydrogen or C.sub.1 to C.sub.6 linear or branched alkyl, e.g., methyl or ethyl; aralkyl, e.g., benzyl; cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; alkyl substituted cycloalkyl, e.g., methylcyclohexyl; C.sub.6 to C.sub.10 aryl, e.g., phenyl unsubstituted or substituted with, for example, methyl, dimethyl, butyl especially isobutyl or phenyl substituted with C.sub.1 to C.sub.4 alkylthio, C.sub.1 to C.sub.4 alkoxy, cyano or halo, e.g., fluoro or chloro; C.sub.1 to C.sub.6 linear or branched alkoxy, e.g., phenoxy or phenoxy substituted with, for example, methyl dimethyl, butyl or isobutyl or phenoxy substituted with C.sub.1 to C.sub.4 alkylthio, C.sub.1 to C.sub.4 alkoxy, cyano or halo; C.sub.1 to C.sub.6 alkylthio, e.g., methylthio; C.sub.2 to C.sub.8 cycloalkylthio; C.sub.6 to C.sub.10 arylthio; C.sub.6 to C.sub.10 arylcarbonyl, e.g., benzoyl; C.sub.4 to C.sub.8 cycloalkenyl, e.g., cyclohexenyl; trifluoromethyl; halo, e.g., fluoro or chloro; C.sub.4 to C.sub.5 heteroaryl, e.g., furyl, pyrrolyl, thienyl; or C.sub.10 to C.sub.14 aryl, e.g., naphthyl or naphthyl substituted with C.sub.1 to C.sub.4 alkyl, e.g., methyl; C.sub.1 to C.sub.4 alkoxy, e.g., ethoxy, halo; or biphenyl unsubstituted or substituted with methyl or halo, especially fluoro.
Preferred compounds of formula I are those of the formula ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are as previously defined and R.sub.5 and R.sub.6 are C.sub.1 to C.sub.4 linear or branched alkyl, C.sub.1 to C.sub.4 linear or branched alkoxy or halo.
The improved process is particularly applicable to 2-(4-isobutylphenyl)propionic acid and especially in obtaining a preponderance of the S(-) isomer.
The process is carried out by using a racemic mixture [a mixture of both the (+) and (-) or dextro and levo rotorary forms] or a mixture containing a preponderance of one of the enantiomers of these carboxylic acids. The use of a 1:1 racemic mixture is preferred. Because the separation of isomers gives rise to a soluble product largely containing one enantiomer and an insoluble product largely containing the other enantiomer, a high purity salt is obtained that requires a minimum number of recrystallizations (usually not more than one) to give a product with exceptional high optical purity at significantly higher yields.
The purified enantiomeric salt obtained from the process of the present invention may be further treated to produce the free aliphatic carboxylic acid thereof by using any conventional means. For example, hydrolysis of the salt with a dilute mineral acid and extraction with a suitable organic solvent produces the purified aliphatic carboxylic acid. Further extraction and recrystallization with a suitable solvent can increase the purity to even greater extent.
The first step in the reaction sequence for the separation of the racemic mixtures used in the present invention is to form a mixture of the aliphatic carboxylic acid with a solvent. The solvent employed to form the mixture is preferably a liquid and inert. Most preferably, but not limited to, such solvents include the aliphatic hydrocarbon solvents, i.e., C.sub.4 to C.sub.14 hydrocarbons, C.sub.1 to C.sub.6 alcohols, nitriles, amides, and halides. Particularly preferred are hexanes, heptanes, octanes and water as such solvent.
The chiral organic nitrogenous base is next added. It forms a more stable salt with the isomers of the aliphatic carboxylic acid. Further, one of the diastereomeric salts formed from the chiral organic nitrogenous base is more soluble in the reaction solution (the solution formed when the chiral base is added to the salt solution), the other, of course, precipitates. The solid crystalline precipitate is readily separated from the solution by conventional techniques, i.e., centrifugation, filtration and the like. It is this material that is used as the starting material for the purification process of the present invention.
It should be noted that the process of the present invention is particularly adapted to the economical conversion of racemic mixtures to the diastereomeric S- or R- component. The method of the present invention essentially provides a solid precipitate enriched in the S-enantiomer and a liquid filtrate enriched in the R-enantiomer. Liberation of the desired S-enantiomer from the precipitated salt is readily accomplished by acidification of the salt with, for example, dilute mineral acid or any other inorganic or organic acid conventionally known to hydrolyze salts of this nature. This procedure leaves the R-enriched filtrate as a by-product. If the desired product is the R-isomer, the filtrate can be treated in a conventional manner to recover the R-isomer. The filtrate, as such, can be racemized via conventional methods and recycled. This mixture can then be reused in the process of the present invention, using the chiral organic base recovered from the above conversion step. Thus, the process of the present invention lends itself readily to a recycling-type of procedure.